A Phase 1 SBIR program of pre-clinical development is proposed focusing on a novel long-acting insulin analog for the basal treatment of diabetes mellitus. Designated Insulin-ZN, our product is a derivative of human insulin containing novel zinc-binding sites at the periphery of the insulin hexamer. The non-classical zinc-binding sites are mediated by paired (i, i +4) histidine substitutions in the A-chain (substitutions GluA4.His and ThrA8.His). Unlike the current market leader among long-acting insulin products (Lantus(R)), Insulin-ZN exhibits negligible cross-binding to the mitogenic Type 1 IGF receptor (IGF-1R). Insulin-ZN offers to patients the potential advantages of once-a-day dosing without concern that enhanced cross-binding to IGF-1R may lead to elevated risk of IGF-1R-related cancers (e.g., of the breast, colon, pancreas, and prostate). Such concerns have recently been raised in studies of >140,000 German patients with Type 2 diabetes mellitus being treated with Lantus(R). The affinity of Insulin-ZN for IGF-1R is at least 30- fold lower than that of insulin glargine, the active ingredient of Lantus(R). The improved receptor-binding selectivity of Insulin-ZN may be especially important in patients with insulin resistance requiring higher doses of insulin to affect glycemic control. We seek to test candidate formulations of Insulin-ZN and to assess its in vivo potency and pharmacokinetics in animal models. Insulin-ZN was invented at Case Western Reserve University and is being developed under license to Thermalin Diabetes, Inc. The principal investigator, who brings to this application four decades of experience in pharmaceutical studies of insulin formulations, was co-inventor of insulin lispro. PUBLIC HEALTH RELEVANCE: Diabetes is increasing in global prevalence. To provide greater convenience, improved glycemic control, and fewer adverse side-effects (all of which result in greater compliance and lower healthcare costs), we have invented a novel long-acting insulin analog (designated Insulin-ZN) that, unlike Lantus(R), exhibits negligible cross-binding to the mitogenic Type 1 IGF receptor, thereby in theory reducing cancer risk. The innovative design of Insulin-ZN exploits the introduction of non-classical pH-dependent zinc-binding sites into the insulin hexamer to create a long-acting subcutaneous depot. This project will complete the pre-clinical proof of concept for Insulin-ZN.